Werner R G, Pommer C H
Biotechnische Produktion, Biberach an der Riss, Fed. Rep. of Germany.
Arzneimittelforschung. 1990 Nov;40(11):1274-83.
Successful development of recombinant DNA-derived pharmaceuticals, a new class of therapeutic agents, is determined by a variety of factors affecting the selection and positioning of the compound under development. For an efficient development it is of utmost importance that the mechanism of action of the compound selected be understood on a molecular level. The compound's potential therapeutical profile and a strong patent position are key positioning considerations, as well as vital elements in shortening the development phase and protecting innovation. Installation of an interdisciplinary project management team, along with a clear definition of team members' responsibilities, is required to avoid delays and improve communication during development. Selection of the organism to be used in production must take into consideration both the structure of the protein and the quality and safety of the final product. New technologies require a considerable investment in new manufacturing facilities and equipment. Often, the decision for such an investment must be made early and with a high degree of uncertainty. Desired product yield, expected dosage, and estimated market potential are the most important considerations in this decision. Following public disclosure of the plan to develop recombinant DNA-derived products, approval of the production plant and expansion or adaptation to the new process and technology may be delayed. For this reason, they should be considered as a critical step in the overall development phase. Recruitment of qualified staff is a time-consuming and critical element of the production process. Its impact on the product timeline should not be underestimated, especially if such technologies are new to the company. The entire production process must be validated in respect to identity, purity, and safety of the product to guarantee constant product quality, as well as for safety aspects in the environment. Adequate in-process and final product controls have to be established and specifications determined for release or rejection of batches for preclinical and clinical studies as well as for marketing. Preclinical testing is limited because recombinant DNA-derived proteins cannot be differentiated from naturally occurring human proteins, and because some proteins are species-specific.
重组DNA衍生药物作为一类新型治疗药物，其成功研发取决于多种影响待研发化合物选择和定位的因素。为了实现高效研发，至关重要的是要在分子水平上理解所选化合物的作用机制。化合物的潜在治疗特性和强大的专利地位是关键的定位考量因素，也是缩短研发阶段和保护创新的重要因素。需要组建一个跨学科项目管理团队，并明确团队成员的职责，以避免研发过程中的延误并改善沟通。生产中所用生物体的选择必须同时考虑蛋白质的结构以及最终产品的质量和安全性。新技术需要在新的生产设施和设备上进行大量投资。通常，必须尽早做出这种投资决策，而且不确定性很高。期望的产品产量、预期剂量和估计的市场潜力是这一决策中最重要的考虑因素。在公开披露开发重组DNA衍生产品的计划后，生产工厂的批准以及对新工艺和技术的扩展或调整可能会延迟。因此，应将它们视为整个研发阶段的关键步骤。招聘合格员工是生产过程中耗时且关键的环节。其对产品时间表的影响不可低估，尤其是当这些技术对公司来说是新的时。整个生产过程必须就产品的身份、纯度和安全性进行验证，以确保产品质量稳定，并确保环境安全。必须建立适当的过程中和最终产品控制措施，并确定用于临床前和临床研究以及上市批次放行或拒收的规格。临床前测试存在局限性，因为重组DNA衍生的蛋白质无法与天然存在的人类蛋白质区分开来，而且有些蛋白质具有物种特异性。
